O-methyl rich fully stabilized oligonucleotides

A double-stranded nucleic acid structure comprising an antisense strand and a sense strand, wherein:

• the antisense strand comprises at least 14 contiguous nucleotides, a 5′ end and a 3′ end, and has complementarity to a target;
• the sense strand comprises at least 13 contiguous nucleotides, a 5′ end and a 3′ end, and has complementarity to the antisense strand;
• the antisense strand comprises at least 85% 2′-O-methyl modifications;
• and
• the nucleotides at positions 2, 14, and 20 from the 5′ end of the antisense strand comprise a non-2′-O-methyl modification or are modified with 2′-F.

A branched oligonucleotide compound capable of mediating RNA silencing in a cell, comprising two or more double-stranded nucleic acids,

• wherein the nucleic acids (N) are connected to one another by one or more moieties selected from a linker (L), a spacer (S), and optionally a branching point (B),
• wherein each double-stranded nucleic acid comprises an antisense strand and a sense strand, wherein each antisense strand comprises at least 14 contiguous nucleotides, a 5′ end and a 3′ end, and at least one antisense strand comprises at least 85% 2′-O-methyl modifications,
• wherein the nucleotides at positions 2, 14, and 20 from the 5′ end of the at least one antisense strand comprise a non-2′-O-methyl modification, and
• wherein one or more nucleotides at positions 1-7 from the 3′ end of at least one antisense strand are connected to adjacent nucleotides via phosphorothioate linkages.